2-hydroxybenzo(b)quinolizines

ABSTRACT

The compounds are 2-hydroxybenzo(b)quinolizines which are useful agents which affect the central nervous system and which can be used as tranquilizing agents to control aggressive antisocial behavior in animals. The compounds may also be used as intermediates in the preparation of pickling agents, mothproofing agents and wood preservatives. Representative of the compounds disclosed are 8,9-dimethoxy-2-hydroxy-2,3,4,6,11,11a-hexahydro1H-benzo(b)quinolizine and 8,9-dimethoxy-2-hydroxy-2-(3&#39;&#39;trifluoromethylphenyl)-2,3,4,6,11,11a-hexahydro-1Hbenzo(b)quinolizine.

United States Patent Suh et al.

[151 3,665,006 51 May 23,1972

[54] 2-HYDROXYBENZO[b]QUINOLIZINES [72] Inventors: John T. Suh, Mequon; Richard A. Schnettler, Milwaukee, both of Wis.

21 Appl. No.: 10,289

[52] U.S. Cl ..260/289 R, 260/283 SA [51 Int. Cl. ..C07d 39/12 [58] Field ofSearch ..260/289, 289A [56] References Cited UNITED STATES PATENTS 3,408,352 10/1969 Hardtmann ..260/289 3,484,443 12/1969 Watthey ..260/289 OTHER PUBLICATIONS Miller, Chem. Abstr., Vol. 71, C01. 37263e, 1969 Bobbitt et al., Jour. Org. Chem., Vol. 33, 2958- 9(1968) Primary ExaminerDonald D1 Daus Attorney-T. F. Kryshak and M. L. Youngs ABSTRACT The compounds are 2-hydroxybenzo[blquinolizines which are useful agents which affect the central nervous system and which can be used as tranquilizing agents to control aggressive antisocial behavior in animals. The compounds may also be used as intermediates in the preparation of pickling agents, mothproofing agents and wood preservatives. Representative of the compounds disclosed are 8,9-dimethoxy-2-hydroxy- 2,3,4,6,l 1,1 la-hexahydrol H-benzo[b]quinolizine and 8,9- dimethoxy-2-hydroxy-2-( 3 -trifluoromethylphenyl 2,3,4,6,l 1,1 la-hexahydrol H-benzo[b]quinolizine.

8 Claims, No Drawings 3 ,665 ,006 1 2 2-HYDROXYBENZO[B]QUINOLIZINES in which R is hydrogen are prepared by dissolving the desired ketone starting material in a lower alkanol such as methanol to DESCRIPTION OF THE INVENTION which sodium borohydride is added. The resulting solution is The compounds f the present invention may be then preferably refluxed for a short period of time, from 1 to represented by the f ll i f l 5 about 3 hours. The solvent is removed from the reaction mixture and the resulting solids recrystallized from isopropyl al- Y 0H cohol. The described process may be illustrated as follows:

wherein Y and Z are the same or different members selected Y Y OH N O NaBH4 Z W. A H

Z do 4 7,

from hydrogen, hydroxy, a halogen such as chloro, bromo or fluoro, trifluoromethyl, a lower alkoxy of one to four carbon atoms such as methoxy, ethoxy or propoxy, sulfamoyl, a lower in which Y and Z are as defined and R is hydrogen. Represenalkyl sulfonamide such as methyl sulfamoyl, and R is selected tative of the compounds to be prepared by this process are the from hydrogen, phenyl, a halogen-substituted phenyl such as following:

p-chlorophenyl, o-chlorophenyl, 3,4-dichlorophenyl, 4- 8,9-dimethoxy-2-hydroxy-2,3,4,6,11,11a-hexahydro-1I-lfluorophenyl, a trifiuoromethyl-substituted phenyl such as 4- be zo[b] uinolizine,

trifluoromethylphenyl, a lower alkoxy-substituted phenyl such 8,9-dih drox -2-hydroxy.2,3,4,6,1 1,1 la-hexahydro-IH- as 4-methoxyphenyl and Ii,4-dimethoxyphenyl, a hydroxy-subb z [b] uin lizine,

stituted phenyl such as 4-hydroxyphenyl and 3,4-dihydrox- 8-chlQfo-2-hydfQxy-2 3 4,6 1 1,1 l -h xah dr .lfl.b n yphenyl, a phenyl-lower alkyl containing seven to 13 carbon bh i li i atoms Such as benzyl, Phenethyl P y p py a 9-chloro-2-hydroxy-2,3,4,6,11,11a-hexahydro-1H-benzo[ halogen-substituted phenyl-lower alkyl such as 3- bhuinolizine,

chlorobenzyl, a trifluoromethyl-substituted phenyl-lower alkyl 8 ifl th 2 h dr .2 3 4 6 1 1 1 1 .h .1H. such as 3-trifluoromethylbenzyl and a lower alkoxy-subbemowhuinolizine,

Stiwled p y alkyl Such as O-methoxybenzyl and 9-trifluoromethyl-2-hydroxy-2,3,4,6,l1,1la-hexahydro-IH- dimethoxybenzyl.

The basic starting materials used for the preparation of the compounds of the present invention are 3,4,1 1,1 latetrahydro-ll-l-benzo[b]quinolizin-2(6H)-ones of the following formula:

benzo[b]quinolizine, l0-fluoro-2-hydroxy-2,3,4,6,1 1,1 1a-hexahydro-1H-benzo[ b]quinolizine, 8-methylsulfamoyl-2-hydroxy-2,3,4,6,l l ,l la-hexahydrolH-benzo[b]quinolizine, and Y 2'hydroxy-2,3,4,6,l 1,1 la-hexahydrol H-benzo[b]quinolizine. The compounds in which R is other than hydrogen are 40 preferably prepared by reacting the ketone starting material with organometallic reagents such as phenyl lithium or a a Grignard reagent. The reactants are advisable combined in an anhydrous solvent such as ethyl ether, tetrahydrofuran or ethyl ether with benzene, and, if desired, the reaction is conm which Y and z are as prevlously defined one method of ducted at reflux temperatures. When the reaction is substanpreparing these compounds is the method described by J. M.

Bobbin and T. E Moore J g Chem. 33 2958 (1962 tially complete water is added to hydrolize the Grignard ad- Representative of the compounds wk'lich may be employed duct to the deslred tertiary alcohol. The resulting product can are the following, then be isolated from the m1xture by conventional means such 89 dimethoxy 34,l 1,1 la tetrahydro lwbenzowlquim as by evaporation of the solvent. The descr1bed process may olizin 2( 6H) 0ne, be illustrated as follows: 8,9-dihydroxy-3,4,1 l ,1 la-tetrahydrol l-l-benzo[b]quin- Y Y H o1izin-2( 6H )-one, I 8-chloro-3,4,1 1 ,1 la-tetrahydro-1H-benz0[b]quinolizinl gg j ff 2(6H)-one, R 9-chloro-3 ,4,1 1,1 la-tetrahydrol H-benzo[ b ]quinolizin- N N 2(6H)-one, Z Z 8-fluoro-3,4,l 1,1la-tetrahydro-lH-benzo[b]quinolizinv T W T 2(6H)-one, 9 fl 3 4 1 1'1 1a teu-ahydm 1H benZ0[b]quino]izin 1n which Y, Z and R are as prev1ously defined and X is a reac- 2(6H )-one, tive halogen. Amongthe Grignard reagents which may be em- 8-trifluoromethyl-3,4,1 1,1 la-tetrahydro-lH-benzo[b]quin- Ployed the following:

olizimzwflyone phenylmagneslum bromide, 9-trifluoromethyl-3,4,l 1,1 la-tetrahydro-lH-benzo[b]quinphenylmagnesium iodide,

o|izin 2(6H) one and 5 4-chlorobenzylmagnes1um bromide, 3,4,1 1,1 la-tetrahydro- 1 H-benzo[b]quinolizin-2(6H)-one. 3y4-dichlowbenzylmagnesium bromide, In the preferred practice of the present invention the combenzylmagnesium bromide, pounds f h fo l 4-methoxybenzylmagnesium bromide,

4-chlorophenylmagnesium bromide, Y 3,4-dichlorophenylmagnesium bromide,

OH 4-methoxyphenyl magnesium bromide, R 4-fluorophenylmagnesium bromide,

4-trifluoromethylphenyl magnesium bromide, N B-trifluoromethylphenyl magnesium bromide, and Z W 3-chlorobenzylmagnesium bromide.

EXAMPLE 3 8 ,9-Dimethoxy-2-hydroxy-2( 4 '-chlorophenyl 2 ,3,4,6,1 1,1 la-hexahydro-l H-benzo[ bJquinolizine In 50 ml. of ether 0.73 g. (0.03 mole) of magnesium is suspended to which 5.7 g. (0.03 mole) of 1-bromo-4- chlorobenzene is added. When the magnesium is dissolved 4.0 g. (0.015 mole) of 8,9-dimethoxy-3,4,11,1la-tetrahydro-1H- benzo[b]quinolizin-2(6l-l )-one and 100 ml. of THF are added. The mixture is refluxed for one hour, poured into 200 ml. of saturated ammonium chloride solution and extracted into chloroform, washed with brine, and dried (Na SO.,). Removal of the solvent affords a dark oil which is chromatographed over 400 g. of silica gel (CHfzbenzenezEtOl-l: 3:6: 1) to afford two isomers. The isomer A is recrystallized from ethanol to afford a solid, m.p. 101l03. The isomer B, also recrystallized from ethanol, affords a solid, m.p. 80-82.

Anal. Calcd. for C H CINO C, 67.28; H, 6.72; N, 3.74.

Found: lsomer A: C, 66.94; H, 6.36; N, 3.87.

Found: lsomer B: C, 67.60; H, 6.69; N, 3.92.

EXAMPLE 4 8,9-Dimethoxy-2-hydroxy-2-( 3 ,4'-dichlorophenyl)- 2,3,4,6,1 1,1 la-hexahydrol H-benzo[b]quinolizine In 20 ml. ether is suspended 0.96 g. (0.04 mole) magnesium to which is slowly added 9.05 g. (0.04 mole) l-bromo-3,4- dichlorobenzene and 2 drops 1,2-dibromoethane. When the magnesium is dissolved 5.0 g. (0.0192 mole) 8,9-dimethoxy- 3,4,1 1 ,1 la-tetrahydro- 1 H-benzo[b]quinolizin-2( 6H )-one and 50 ml. tetrahydrofuran are added. The mixture is refluxed 3 hours, poured into 10 percent ammonium chloride: solution and extracted into chloroform, washed with water, and dried. Removal of solvent affords a dark oil which is chromatographed over silica gel (400 g.; ChfzEgOzEtOl-l; 3:6: 1 Taking 250 ml. fractions the carbinol is obtained which is then recrystallized from ethanohwater; to yield 8,9-dimethoxy-2- hydroxy-2-( 3 ,4-dichlorophenyl )-2,3,4,6,l 1,1 la-hexahydroll-l-benzo[b]quino1izine, m.p. 201-203.

Anal. Calcd. for C ,H ,,NO Cl C, 61.61; H, 5.91; N, 3.42.

Found: C, 61.42; H, 5.74; N, 3.43.

EXAMPLE 5 8,9-Dimethoxy-Z-hydroxy-Z-(4"methoxyphenyl)- 2,3 ,4,6,1 1,1 la-hexahydro-l H-benzo[ b]quinolizine The Grignard reagent is prepared in the usual manner from 1.2 g. (0.05 g-atom) of magnesium and 9.4 g. (0.05 mole) of p-bromoanisole in 50 ml. of ether. When the magnesium is dissolved 6.5 g. (0.025 mole) of 8,9-dimethoxy-3,4,l 1,1 latetrahydro-lH-benzo[b]quinolizin-2(6H)-one is added along with 100 ml. of THF. The solution is refluxed for 2 hours, cooled and poured into 200 ml. of saturated ammonium chloride solution, extracted with chloroform, and dried over Na SO Removal of the solvent leaves 11.1 g. of a brown oil which is chromatographed over 300 g. of silica gel (60 percent benzene:30 percent chloroformzlO percent ethyl alcohol) to afford 0.8 g. of isomer A which is crystallized twice from isopropyl alcohol, m.p. 1 14l 16.

Anal. Calcd. for C H NO,: C, 71.51; H, 7.37; N, 3.80.

Found: lsomer A: C, 71.69; H, 7.36; N, 3.97.

lsomer B: (EX 11-588) N, 3.46.

EXAMPLE 6 8 ,9-Dimethoxy-2-hydroxy-2-( 4-fluorophenyl 2,3,4,6,1 1 ,l 1a-hexahydrol H-benzo[b]quinolizine The Grignard reagent is prepared from 1.2 g. (0.05 mole) of magnesium and 8.8 g. (0.05 mole) of p-bromofluorobenzene in 50 ml. of dry ether. When the magnesium is dissolved, 6.5 g. (0.025 mole) of 8,9-dimethoxy-3,4,l 1,1 la-tetrahyclro-IH- benzo[b]quinolizin-2(6H )-one and 100 ml. of THF are added and the solution is refluxed 2 hours, cooled, poured into 200 ml. of saturated ammonium chloride solution, extracted into chloroform, dried over M1 50 and the solvent removed to leave a dark oil which is chromatographed over 400 g. of silica gel (benzenezchloroformzethanol; 6:3:1) to afford a tan solid which is crystallized from isopropyl alcohol to give 8,9- dimethoxy-2-hydroxy-2-(4'-fluorophenyl)-2,3,4,6, l 1 ,1 1ahexahydro-l-benzo[b]quinolizine as a white solid, m.p.

129-130Anal. Calcd. for C l-l FNo C, 70.57; H, 6.84; N, 3.92.

Found: C, 70.36; H, 7.14; N, 3.85.

EXAMPLE 7 8,9-Dimethoxy-2-hydroxy-(4'-trifluoromethylphenyl 2,3 ,4,6,1 1,1 la-hexahydro-1H-benzo[b]quinolizine The Grignard reagent is prepared in the conventional manner from 1.2 g. (0.05 g-atom) of magnesium and 11.3 g. (0.05 mole) of p-bromobenzotrifluoride in 50 ml. of THF. When the magnesium is dissolved 6.5 g. (0.025 mole) of 8,9- dimethoxy-3 ,4,1 1,1 la-tetrahydro- 1 H-benzo[b]quinolizin- 2(6H )-one is added along with ml. of THF. The solution is refluxed for 2 hours, cooled and poured into 200 ml. of saturatedammonium chloride solution, extracted with chloroform and dried over Na SO Removal of the solvent leaves an oil which is chromatographed over 300 g. of silica gel (6 percent benzene:30 percent chloroform: 10 percent ethyl alcohol) to afford a single isomer which is recrystallized from isopropyl alcohol, m.p. 194l95.

Ana]. Calcd. for C H F NO C, 64.86; H, 5.94; N, 3.44.

Found: C, 65.10; H, 6.16; N, 3.45.

EXAMPLE 8 8 ,9-Dimethoxy-2-hydroxy-2-( 3 -trifluoromethylphenyl)- 2,3 ,4,6,1 1,] la-hexahydrol l-l-benzo[b]quinolizine The Grignard reagent is prepared in the conventional manner from 2.9 g. (0.12 g-atom) of magnesium and 27.0 g. (0.12 mole) of m-bromobenzotrifluoride in 100 ml. of THF. When the magnesium is dissolved, 26.1 g. (0.1 mole) of 8,9- dimethoxy-3 ,4,1 1,1 1a -tetrahydrol H-benzo[b )quinolizin- 2(6H)-one and 100 ml. of THF are added. The solution is stirred at room temperature for 2 hours, poured into 200 ml. of saturated ammonium chloride solution and extracted into chloroform. Removal of the solvent leaves 47.4 g. of a dark solid, of which 24.0 g. are chromatographed over 600 g. of silica gel (60 percent benzenez30 percent chloroform: 10 percent ethyl alcohol) to afford isomer A, recrystallized from benzene/petroleum ether to afford 8,9-dimethoxy-2-hydroxy- 2-( 3 '-trifluoromethylphenyl )-2,3 ,4,6,l 1,1 la-hexahydrol H- benzo[b]quinolizine as a beige powder, m.p. -l58.

Anal. Calcd. for C,,H,.,F,N0,: C, 64.86; H, 5.94; N, 3.44.

Found: C, 65.03; H, 6.17; N, 3.66.

EXAMPLE 9 8,9-Dirnethoxy-2-hydroxy-2-benzyl-2,3,4,6,1 1,1 la-hexahydro- 1 H-benzolb1quinolizine The Grignard reagent is prepared following the usual procedure using 1.2 g. (0.05 mole) of magnesium and 8.6 g. (0.05 mole) of a-bromotoluene in 50 ml. of ether. After addition of 6.5 g. (0.025 mole) of 8.9-dimethoxy-3,4,l 1,1 10- tetrahydro-lH-benzo[b]quino1izin-2( 6H)-one and 100 ml. of THF, the solution is refluxed 2 hours, poured into ammonium chloride solution, extracted into chloroform, washed with saturated brine and dried (Na SO Removal of the solvent leaves a dark oil which is chromatographed (400 g. silica gel, EtOAc:EtOH; 9: 1) to afford a yellow glass which is recrystallized from isopropyl alcohol to afford 8,9-dimethoxy-2- hydroxy-2-benzyl-2,3 ,4,6, l 1 l la-hexahydrol H-benzo [b]quinolizine as a white crystalline solid, m.p. 159-161.5.

Anal. Calcd. for C H NO C, 74.75; H, 7.70; N, 3.97.

Found: C, 74.87; H, 7.72; N, 4.10.

EXAMPLE l0 8,9-Dimethoxy-2-hydroxy- 2-( 3 -chlorobenzyl 2,3,4,6,l 1 ,1 la-hexahydro-l H-benzo[b]quinolizine The Grignard reagent is prepared in the usual way using 1.2 g. (0.05 mole) of magnesium and 10.2 g. (0.05 mole) of 3- chlorobenzyl bromide in 50 ml. of ether. After addition of 6.5 g. (0.025 mole) of 8,9-dimethoxy-3,4,11,11a-tetrahydro-1H- benzo[b]quinolizin-2( 6H)-one and 100 ml. of THF the solution is refluxed 2 hours, cooled, poured into 200 ml. of ammonium chloride solution, extracted into chloroform, washed with brine, and dried (Na SO Removal of the solvent leaves an amber oil which is chromatographed over 400 g. of silica gel (chloroform:benzenecethanol; 6:3: 1) to afford a brown solid which is recrystallized two times from isopropyl alcohol to afford 8,9-dimethoxy-2-hydroxy-2-(3-chlorobenzyl)- 2,3,4,6,1 1,1 la-hexahydro-lH-benzo[b]quinolizine as white crystals, m.p. 93-95.

Anal. Calcd. for c,,n,,Nc1o,; C, 68.12; H, 6.75.

Found: C, 67.87; H, 6.99.

EXAMPLE 1 l 8 ,9-Dimethoxy-2-hydroxy-2-( 2-trifluoromethylphenyl 2,3 ,4,6,l 1,1 la-hexahydro- 1 H-benzo[b]quinolizine Magnesium (2.16 g., 0.089 mole) is suspended in about 25 ml. dry ether and 20 g. (0.089 mole) o-bromobenzotrifluoride slowly added with 225 ml. ether. After the magnesium has dissolved 18.3 g. (0.07 mole) 8,9-dimethoxy-3,4,l 1,1 latetrahydro-1H-benzo[b]quinolizin-2(6H)-one is added with 80 ml. dry THF. The mixture is refluxed 15 hours, cooled and quenched with 200 ml. saturated ammonium chloride solution. The organic layer is diluted with ethyl ether, washed with water, and extracted with dilute hydrochloric acid. The acid is washed with ether, neutralized with sodium hydroxide solution, extracted with chloroform and dried. Evaporation of the chloroform gives a gum which is chromatographed over 300 g. silica gel (ChfzEgOzEtOH; :4: 1) to give 8,9-dimethoxy-2- hydroxy-2-( 2-trifluoromethylphenyl)-2,3 ,4,6,1 1,1 la-hexahydro-ll-l-benzo[b]quinolizine as a white solid which upon recrystallization from benzene melts at 154-157.

Anal. Calcd. for C H F NO C, 64.86; H, 5.94; N, 3.44. Found: C, 65.34; H, 6.24; N, 3.31. We claim: 1. A compound of the formula wherein Y and Z are hydroxy or lower alkoxy of one to four carbon atoms, and R is selected from phenyl, chlorophenyl, dichlorophenyl, fluorophenyl, trifluoromethyl phenyl, and lower alkoxy phenyl.

2. The compound of claim 1 in which Y and Z are methoxy and R is hydrogen.

3. The compound of claim 1 in which Y and Z are methoxy and R is phenyl.

4. The compound of claim 1 in which Y and Z are methoxy and R is chlorophenyl.

5. The compound of claim 1 in which Y and Z are methoxy and R is dichlorophenyl.

6. The compound of claim 1 in which Y and Z are methoxy and R is fluorophenyl.

7. The compound of claim 1 in which Y and Z are methoxy and R is benzyl.

8. The compound of claim 1 in which Y and Z are methoxy and R is 3'-trifluoromethylphenyl. 

2. The compound of claim 1 in which Y and Z are methoxy and R is hydrogen.
 3. The compound of claim 1 in which Y and Z are methoxy and R is phenyl.
 4. The compound of claim 1 in which Y and Z are methoxy and R is chlorophenyl.
 5. The compound of claim 1 in which Y and Z are methoxy and R is dichlorophenyl.
 6. The compound of claim 1 in which Y and Z are methoxy aNd R is fluorophenyl.
 7. The compound of claim 1 in which Y and Z are methoxy and R is benzyl.
 8. The compound of claim 1 in which Y and Z are methoxy and R is 3''-trifluoromethylphenyl. 